Phenotypes Associated with This Genotype

Genotype
MGI:2451081

• Allelic Composition: Lipa^tm1Hodu/Lipa^tm1Hodu
• Genetic Background: involves: 129P2/OlaHsd * CF-1

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

Lipid storage in the liver and small intestine and decrease in subcutaneous white adipose tissue in Lipa^tm1Hodu/Lipa^tm1Hodu mice as they age

mortality/aging

premature death ( J:68812 )

• appear normal at birth and survive into adulthood but die at ages of 7-8 months

liver/biliary system

abnormal liver morphology ( J:49674 )

• livers were yellow early with the color deepening to orange with age

abnormal liver sinusoid morphology ( J:49674 )

• mild compression of sinusoidal spaces

abnormal Kupffer cell morphology ( J:68812 )

• progressive cholesteryl ester and triglyceride storage in Kupffer cells

• by 3-8 months, significant hypertrophy and hyperplasia of Kupffer cells

hepatosplenomegaly ( J:68812 )

• progressive hepatosplenomegaly with age

increased liver weight ( J:49674 , J:68812 )

• heavier than normal livers (J:49674)

• liver weight increased 6 fold over controls at 8 months of age (J:68812)

increased liver cholesterol level ( J:49674 )

• cholesterol esters were elevated 32 fold in the liver

increased liver triglyceride level ( J:49674 )

abnormal hepatocyte morphology ( J:49674 , J:68812 )

• slightly enlarged (J:49674)

• vacuolated with oil drops and isotrophic crystals (J:49674)

• significant vacuolation and neutral lipid storage in hepatocytes at 1.5 months (J:68812)

• percentage of storage cells that are hepatocytes decreases with age with a switch to predominantly Kupffer cell storage by 3-8 months (J:68812)

hepatic steatosis ( J:68812 )

• lipid storage cells in liver appear to be macrophage

• lipid is mostly in lysosomes

immune system

abnormal Kupffer cell morphology ( J:68812 )

• progressive cholesteryl ester and triglyceride storage in Kupffer cells

• by 3-8 months, significant hypertrophy and hyperplasia of Kupffer cells

abnormal alveolar macrophage morphology ( J:101217 )

• massive neutral lipid accumulation in bronchoalveolar macrophages evident at 2 months or later

• at 2 months, bronchoalveolar macrophages appear foamy; some alveolar macrophages aggregate to form small patches and fill the alveolar lumen

• fewer bronchoalveolar macrophages are found at 2 months but steadily increase in number with age progression

abnormal spleen morphology ( J:49674 , J:68812 )

• yellow in color (J:49674)

• cholesterol esters much elevated (J:49674)

• triglyceride levels decreased (J:49674)

• accumulation of lipid storage cells in spleen at 6 months (J:68812)

enlarged spleen ( J:68812 )

• splenomegaly first noted at 3 months

• progressive hepatosplenomegaly with age

hepatosplenomegaly ( J:68812 )

• progressive hepatosplenomegaly with age

increased spleen weight ( J:49674 , J:68812 )

• heavier than normal (J:49674)

• spleen weight increased 4.4X of controls at 8 months of age (J:68812)

enlarged mesenteric lymph nodes ( J:68812 )

• enlargement of a single mesenteric lymph node at 2 months due to lipid storage in macrophages

• size may be up to 2.5g

chronic inflammation ( J:101217 )

• chronic inflammation in the lung

lung inflammation ( J:101217 )

• progressive neutrophil infiltration in the alveolar region first evident at 2 months of age

• steady increase in the number of foamy bronchoalveolar macrophages from 2 to 6 months of age

homeostasis/metabolism

increased circulating insulin level ( J:68812 )

• plasma insulin levels increased 6.7X after glucose load for 30 min

insulin resistance ( J:68812 )

• significantly increased insulin resistance

• lower basal glucose levels

• glucose levels after glucose loading about equivalent to that seen in controls

abnormal lipid level ( J:68812 )

• tissue storage of cholesteryl ester and triglyceride progressively increases with age

• however, plasma cholesterol and triglyceride levels are normal

decreased circulating HDL cholesterol level ( J:68812 )

• decreased HDL levels and HDL with faster electrophoretic mobility

increased circulating LDL cholesterol level ( J:68812 )

increased circulating free fatty acids level ( J:68812 )

• after overnight fasting, plasma nonesterified fatty acid levels are significantly elevated at both 2 and 4 months of age

increased liver cholesterol level ( J:49674 )

• cholesterol esters were elevated 32 fold in the liver

increased liver triglyceride level ( J:49674 )

adipose tissue

absent subcutaneous adipose tissue ( J:68812 )

• at 8 months

decreased subcutaneous adipose tissue amount ( J:68812 )

• subcutaneous white adipose tissue is present at 1.5 months but decreases significantly at 5 months and disappears by 8 months

decreased white adipose tissue amount ( J:68812 )

• significant reduction of white adipose tissue at 1.5 months with marked size heterogeneity in adipocytes

• undetectable white adipose tissue at 4 months

abnormal brown adipose tissue morphology ( J:68812 )

• at 4 months, brown adipose tissue is histologically similar to white adipose tissue with increased lipid droplet size in the cells

decreased brown adipose tissue amount ( J:68812 )

• lacked brown fat at 6 months although it was present at 1 month

• however, no significant differences in nonstressed and stressed core body temperature relative to wild-type

increased brown fat cell lipid droplet size ( J:68812 )

• increased lipid droplet size in brown fat cells

abnormal white fat cell size ( J:68812 )

• marked size heterogeneity in adipocytes at 1.5 months of age

decreased epididymal fat pad weight ( J:68812 )

• significant reduction in the amount of epididymal fat at 6 months

abnormal inguinal fat pad morphology ( J:68812 )

• complete absence of inguinal white adipose tissue at 6 months

abnormal retroperitoneal fat pad morphology ( J:68812 )

• complete absence of retroperitoneal white adipose tissue at 6 months

abnormal interscapular fat pad morphology ( J:68812 )

• complete absence of interscapular white adipose tissue at 6 months

digestive/alimentary system

abnormal intestine morphology ( J:49674 )

• cholesterol esters were considerably elevated

abnormal intestinal mucosa morphology ( J:49674 )

• vacuolation and oil drops seen in villi of the mucosal lining

abnormal small intestine morphology ( J:68812 )

• progressive discoloration of the small intestine in a proximal to distal fashion

• progressive lipid storage in the small intestine with increasing age

abnormal duodenum morphology ( J:68812 )

• the duodenum displays a yellow color with increasing age

abnormal jejunum morphology ( J:68812 )

• the jejunum displays a cream white color with increasing age

abnormal small intestinal villus morphology ( J:68812 )

• progressive lipid storage in lamina propria of intestinal villi in cells that are proliferated macrophages

endocrine/exocrine glands

abnormal adrenal gland morphology ( J:49674 )

• vacuolation, oil drops and anisotrophic crystals found

renal/urinary system

pale kidney ( J:68812 )

• paler in color than normal but of normal weight

growth/size/body

decreased body weight ( J:49674 )

• certain founder lines weighed about 15-20% less than controls at 4 weeks

• decreased weight not seen in all lines

• weights were all normal at 8 weeks of age

increased liver weight ( J:49674 , J:68812 )

• heavier than normal livers (J:49674)

• liver weight increased 6 fold over controls at 8 months of age (J:68812)

enlarged spleen ( J:68812 )

• splenomegaly first noted at 3 months

• progressive hepatosplenomegaly with age

hepatosplenomegaly ( J:68812 )

• progressive hepatosplenomegaly with age

increased spleen weight ( J:49674 , J:68812 )

• heavier than normal (J:49674)

• spleen weight increased 4.4X of controls at 8 months of age (J:68812)

hematopoietic system

abnormal Kupffer cell morphology ( J:68812 )

• progressive cholesteryl ester and triglyceride storage in Kupffer cells

• by 3-8 months, significant hypertrophy and hyperplasia of Kupffer cells

abnormal alveolar macrophage morphology ( J:101217 )

• massive neutral lipid accumulation in bronchoalveolar macrophages evident at 2 months or later

• at 2 months, bronchoalveolar macrophages appear foamy; some alveolar macrophages aggregate to form small patches and fill the alveolar lumen

• fewer bronchoalveolar macrophages are found at 2 months but steadily increase in number with age progression

abnormal spleen morphology ( J:49674 , J:68812 )

• yellow in color (J:49674)

• cholesterol esters much elevated (J:49674)

• triglyceride levels decreased (J:49674)

• accumulation of lipid storage cells in spleen at 6 months (J:68812)

enlarged spleen ( J:68812 )

• splenomegaly first noted at 3 months

• progressive hepatosplenomegaly with age

hepatosplenomegaly ( J:68812 )

• progressive hepatosplenomegaly with age

increased spleen weight ( J:49674 , J:68812 )

• heavier than normal (J:49674)

• spleen weight increased 4.4X of controls at 8 months of age (J:68812)

behavior/neurological

increased food intake ( J:68812 )

• at 4 months, male homozygotes display a similar average body weight relative to wild-type males; however, both male and female homozygotes exhibit a significantly higher food intake relative to wild-type

respiratory system

lung inflammation ( J:101217 )

• progressive neutrophil infiltration in the alveolar region first evident at 2 months of age

• steady increase in the number of foamy bronchoalveolar macrophages from 2 to 6 months of age

abnormal lung morphology ( J:68812 )

• accumulation of lipid storage cells in lung macrophages at 6 months

abnormal alveolar macrophage morphology ( J:101217 )

• massive neutral lipid accumulation in bronchoalveolar macrophages evident at 2 months or later

• at 2 months, bronchoalveolar macrophages appear foamy; some alveolar macrophages aggregate to form small patches and fill the alveolar lumen

• fewer bronchoalveolar macrophages are found at 2 months but steadily increase in number with age progression

increased club cell number ( J:101217 )

• striking Clara cell hypertrophy and hyperplasia in the conducting airways at 6 months

abnormal pulmonary alveolus morphology ( J:101217 )

• at 2 months, some small alveolar areas display minor structural remodeling

• severe alveolar structure remodeling and cell proliferation is evident in larger areas by 6 months

abnormal type II pneumocyte morphology ( J:101217 )

• massive neutral lipid accumulation in alveolar type II epithelial cells evident at 2 months or later

increased type II pneumocyte number ( J:101217 )

• at 6 months, the numbers of alveolar type II epithelial cells are increased in areas of alveolar structure remodeling

emphysema ( J:101217 )

• increased air space and reduced alveolar surface in some lung areas with age progression

• severe heterogeneous pulmonary emphysema at 6 months

nervous system

abnormal choroid plexus morphology ( J:68812 )

• accumulation of lipid storage cells in the epithelium of choroid plexus at 6 months

cardiovascular system

abnormal liver sinusoid morphology ( J:49674 )

• mild compression of sinusoidal spaces

abnormal Kupffer cell morphology ( J:68812 )

• progressive cholesteryl ester and triglyceride storage in Kupffer cells

• by 3-8 months, significant hypertrophy and hyperplasia of Kupffer cells

integument

absent subcutaneous adipose tissue ( J:68812 )

• at 8 months

decreased subcutaneous adipose tissue amount ( J:68812 )

• subcutaneous white adipose tissue is present at 1.5 months but decreases significantly at 5 months and disappears by 8 months

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
lysosomal acid lipase deficiency		DOID:0080217	OMIM:PS278000	J:49674
Wolman disease		DOID:14497	OMIM:620151	J:49674